SUMMARY

Lawyers and scientists are not merely proverbial ships passing in the night; they live on different planets mentally. As a long-time environmental lawyer and law professor who has been happily married to a distinguished toxicologist, Gail Charnley PhD, for over two decades, I have come to see how our professional training influences us to see the world differently. In this essay, I try to explain the difference between how lawyers and scientists view the world and significance of those differences for risk regulation, including the regulation of per- and polyfluoroalkyl substances (PFAS).

SUMMARY

By mid-year 2024, the United States Environmental Protection Agency (EPA) had finalized two major, economically significant regulations on per- and polyfluoroalkyl substances (PFAS) in addition to multiple other important PFAS reporting rules. These rulemakings were finalized after EPA received numerous comments on its draft positions. Although some comments supported the EPA’s actions, other comments challenged many aspects of the EPA’s proposals, including the underlying science, legal justifications, and cost implications. These major regulations have been challenged and will likely be litigated in the courts.

SUMMARY

Threshold and linear approaches to quantitative risk assessment are two fundamentally different paradigms that have coexisted for decades, primarily for noncancer and cancer risks, respectively. There have been several efforts in the risk assessment community over the years to “harmonize” cancer and noncancer risk assessment into a single unified approach. Two notable recent proposals for this are those by (1) the US National Academy of Sciences (NAS) and (2) the World Health Organization’s International Programme on Chemical Safety (WHO/IPCS). Both have recommended alternatives to traditional approaches for noncancer risk assessment. Herein, we review the salient aspects and ambitions of these two approaches to harmonizing cancer and noncancer dose–response analysis—the NAS “bottom-up” and the WHO/IPCS “top-down” proposals—focusing on how they apply to noncancer risk evaluation. We articulate issues and caveats and explore additional information needs. We also address how these proposals deal with the long-held concept in toxicology of exposure thresholds for noncancer effects, below which any substantial impact of exposures is not expected. We conclude there is solid evidence for the existence of thresholds and that the approach of estimating variation in susceptibility in these methods ought not be applied to low risk levels and very low exposures, since any such application would be expected to give answers that are unreliable and contingent mainly on the assumptions made rather than on the data about the agent’s actual dose–response properties. Unless and until thresholds are disproven or the reliability of these alternative methods improves, threshold-based approaches to noncancer risk assessment remain the most scientifically defensible.

SUMMARY

Regulatory authorities in the field of environmental health often grapple with decision-making in the face of scientific uncertainty and rapidly emerging data. The identification of per- and polyfluoroalkyl substances (PFAS) contamination in drinking water sources in Israel, and the need for rapid decision-making on PFAS drinking water standards, is one such example. The Water Authority, which is responsible for management of the water sector in Israel, first discovered PFAS contamination in groundwater in 2019. The Ministry of Health (MOH), which is responsible for drinking water quality, began measuring PFAS compounds in 2020. As of the end of 2024, the MOH has measured nine PFAS compounds in over 375 drinking water wells, 14.7% of which have at least one detected PFAS compound. This manuscript reviews four considerations taken into account in the decision on guideline values for PFAS: toxicological threshold, consideration of current worldwide regulatory standards, practical achievability, and analytical capacity. Based on these considerations, the MOH adopted Health Canada’s 2018 maximum acceptable concentrations in drinking water for perfluorooctanoate (PFOA) and perfluorooctane sulfonic acid (PFOS) as an interim guideline value. Subsequently, the MOH decided to adopt the EU Drinking Water Directive standards on PFAS, which include 20 PFAS compounds, and which will enter into force in 2026. To date, drinking water supply has been discontinued from four wells, and another 10 drinking water wells will be discontinued or will require treatment once the stricter standard enters force. Quarterly or annual monitoring for tens of wells is required, depending on measured PFAS concentrations. In addition to ongoing monitoring of PFAS in drinking water wells, the MOH is conducting a human biomonitoring (HBM) study to measure PFAS in blood in an adult population and is involved in work developing HBM guideline values, as part of the Partnership for Chemical Risk Assessment (PARC).

SUMMARY

United States federal agencies charged with protection of human health and the environment, such as the United States Environmental Protection Agency, aspire to use “best available science,” “follow the science,” and make decisions based on the “weight of the evidence.” However, risk-based regulatory decisions often are judgment calls and even policy choices that depend on how the decision-maker looks at and weighs the scientific evidence through the lens of programmatic or even personal preferences. Agencies must take action even in the absence of definitive science and often are given significant discretion when making risk-based decisions. However, courts may pay close attention to statutory language that puts constraints on how agencies are to exercise their discretion. The purpose of this brief essay is to explain to the risk assessment community how risk assessments are used in agency decision-making. I then discuss how courts may review risk-based agency decisions and the potential implications for per- and polyfluoroalkyl substances regulatory actions that are currently being challenged in court.

SUMMARY

Recent risk assessments for perfluorooctanoic acid (PFOA) from different governmental agencies have resulted in estimates of safe exposure that vary by more than 5 orders of magnitude, primarily due to different conclusions regarding the reliability of associations reported in human epidemiological studies at exposures far below those associated with effects in animal studies. To address this disparity, an international collaboration of scientists was facilitated by the Alliance for Risk Assessment (ARA), with the goal of recommending a range of safe human exposure levels to PFOA. The ARA review relied on previous agency evaluations of the quality of studies and focused on the consideration of mechanistic information regarding the potential modes of action for PFOA toxicity to determine both the relevance of the effects reported in animal studies and the plausibility of associations reported in epidemiological studies. The collaboration concluded that the current evidence from human epidemiological studies is inadequate to serve as a basis for a safe PFOA dose level. The recommended range of safe exposures provides an intermediate position between the extremes of different agency values.

Summary

For more than a decade, the Alliance for Risk Assessment (ARA) has hosted a workshop series entitled “Beyond Science and Decisions” to explore and promote advances in risk assessment per the findings of the National Academy of Sciences (National Academy of Sciences, 2009, Science and decisions: Advancing risk assessment, Washington, D.C). Fourteen multi-day workshops, each consisting of multiple case studies, have been conducted to date. In 2023, an entire workshop was devoted to exploring the greater than 100,000-fold differences in international Health-Based Guideline Values (HBGVs) established for perfluorooctanoate (PFOA). The objective of this case study was twofold: (1) to examine the underlying data sets and assumptions used in the hazard identification and dose-response assessments for PFOA conducted by eight different international groups, and (2) to identify productive strategies for narrowing the range of disparate PFOA health values in order to achieve global harmonization. A science panel of experts in risk assessment, several with extensive experience in the assessment of PFOA and related chemicals, contributed to this examination. Overall, workshop discussions focused on an array of science, policy, legal, and economic considerations that may be driving the extraordinary divergence in values. Clear distinctions were found among agencies in how data were interpreted and integrated, coupled with varying applications of uncertainty factors, resulting in vastly different HBGVs worldwide for PFOA. Workshop recommendations include value-added methodological improvements among government agencies, and the need for international harmonization, recognizing that such differences can impede effective risk management and public communication efforts.

Summary

Federal North American safe doses for the noncancer toxicity of perfluorooctanoate (PFOA) are sufficiently different that national authorities should work together to come up with a single value or perhaps a reasonable range. This range should include an appropriate measure for interspecies extrapolation depending on the critical effect, such as the maximum blood concentration, average blood concentration during a critical time, or area under the blood concentration–time curve. Available human clinical data for PFOA allows a comparison of kinetics between experimental animals and humans and should also be considered in the development of PFOA safe doses, since this may allow harmonization of disparate risk values.

Summary

The regulatory histories of dioxins and per- and polyfluoroalkyl substances (PFAS) reveal notable parallels, both shaped by early toxicological concerns and advances in chemical detectability that preceded comprehensive epidemiological validation. This paper examines how initial risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) relied heavily on high-dose animal studies and limited human data, leading to stringent regulations and significant remediation efforts that were later questioned by findings from long-term epidemiological studies. A similar course can be anticipated for PFAS, where regulatory actions such as the setting of extremely low safe drinking water standards have been established despite substantial scientific uncertainties about health effects at environmentally relevant exposure levels. By comparing toxicological mechanisms, dose–response relationships, and regulatory strategies, this analysis identifies important factors that put into question the reliance on precautionary principles without a full evaluation of the uncertainties surrounding each of the alleged adverse health effects. The experience with dioxin regulation provides a basis for recommending that PFAS regulatory bodies adopt a more adaptive strategy, one that emphasizes evolving scientific evidence, careful interpretation of low–dose responses, and greater reliance on relevant human epidemiological data rather than conservative extrapolations primarily from animal studies. This paper suggests that if the scientific and regulatory community reflects on the experience with dioxins, the United States and other nations can potentially save billions by not setting unnecessarily low PFAS regulatory standards while still achieving a theoretical reduction in the possible risks to public health.

SUMMARY

Various national and international agencies have evaluated the available information on per- and polyfluoroalkyl substances (PFAS) to determine no observed adverse effect levels (NOAELs), tolerable daily intake (TDIs) and drinking water standards. In Europe, this includes the German drinking water commission,¹ the European Food Safety Agency (EFSA),² European Chemicals Agency (ECHA)³ as well as the World Health Organization (WHO).⁴ Health-based guidance values e.g. tolerable weekly intake (TWI) appear to largely depend on what information was considered to be relevant and robust. For both, WHO and EFSA, there is the impression that too little consideration was given to the statistical, biological and experimental design robustness of the data sets that were employed.

SUMMARY

The concept of the adverse outcome pathway (AOP) has evolved since inception. Recent advances include a variety of methods for developing quantitative AOPs (qAOPs). The goal is prediction of adverse outcomes from a range of stressors that activate molecular initiating events (MIEs) that in turn trigger a sequence of key events (KEs) leading ultimately to the adverse outcome (AO). Inherent in qAOPs is the implicit assumption of probabilities of transition along this sequence of key event relationships (KERs) based on the degree of activation of the MIE and each subsequent KE. These probabilities are the basis of the KER tipping points and are a function of not only the dysregulation induced by the stressor but also adaptation or resilience of the organism to counter this dysregulation. Two groups of qAOPs are considered here. The first group relies on data and systems biology modeling, an effort dependent on data at all levels of organization including molecules, cells, tissue, organs, organisms, and populations. The second group use methods that are much less data-dependent and are based on certain types of Bayesian networks (BNs). The difficulty with reconciling the biology inherent in the AOP concept with a purely statistical technique such as BNs is the presence of feedback control loops in biological systems that are inconsistent with the one-way information flow permitted in BNs. However, recent developments in BNs may permit such feedback loops. Here we envision a prediction model for qAOPs that depends on newer types of BNs along with a time-dynamic model to estimate the probabilities of exceeding tipping points. Such a model has not yet been developed, but several qAOPs developed with BNs seem ripe for testing this model.

Summary

This article focuses on the Monographs Program, established to address the growing need for cancer classifications of chemicals and other agents. Part I provides an overview of the Program, its global impact, and how International Agency for Research on Cancer’s (IARC) cancer classifications are relied on by U.S. regulatory agencies. Part II discusses two controversial cancer classification decisions involving glyphosate and aspartame, both of which serve to showcase the Monographs Program’s persistent and controversial decision-making process. Indeed, the Program’s cancer classifications continue to roil U.S. federal agencies.

Abstract

The key characteristics of carcinogens (KCCs) embraced by the International Agency for Research on Cancer (IARC) have generated considerable discussion. KCCs provide a basis for organizing information, which is inherently attractive to those seeking to simplify the complex process of cancer hazard identification and risk assessment. However, guidance on integrating evidence for decision-making from KCCs is limited and variable. Used in isolation, KCCs do not predict cancer classifications, and additional evidence is presented demonstrating KCCs can result in mislabeling when compared with IARC and U.S. Environmental Protection Agency (EPA) cancer classifications. Scientific understanding of the multifaceted molecular and cellular processes and dose-dependent transitions involved in chemical carcinogenesis is today vastly superior to what it was a half-century ago – or even 20 years ago. It is imperative that these advances in knowledge be applied to risk assessments so that public health can be protected, and at the same time societal benefits of natural and synthetic chemicals can be realized. The forward evolution of the scientific understanding of cancer and risk assessment has consistently been in the direction of greater complexity, and rigorous application of hypothesis testing and causal analysis. Without an integration into this richer tapestry of scientific information and analyses, reliance on simplistic approaches to cancer assessment and regulation, such as the Delaney Clause or use of KCCs in isolation, is decidedly in the wrong direction. Herein, we propose a return to the fundamental scientific principle of hypothesis generation and testing using four previously described and archetypal chemical carcinogenesis modes of action (MOA). We provide an example of an evolved causal evidence scoring system that allows comparison of the extent to which the evidence supports each hypothesized MOA to identify the likely operative MOA so that this likely operative MOA and associated toxicity values can then be taken forward in risk assessments.

Summary

This paper presents a summary of presentations at the Alliance for Risk Assessment (ARA) Workshop XIV held on October 17–19th, 2023, in Washington, DC, focusing on the health risk-assessment and regulation of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and other per- and polyfluoroalkyl substances (PFAS). The main topics were as follows:

• Toxicological understanding and safe dose: Workshop participants felt that efforts by different regulatory agencies to derive a safe dose for PFOA and other PFAS should be harmonized. Currently, the acceptable daily intakes estimated by various expert-groups differ by up to 1,000-fold. Over time, mechanistic insights in understanding PFAS toxicity may better inform estimates of safe doses.

• Regulatory concerns: The United States Environmental Protection Agency (EPA) finalized drinking water regulations for PFOA, PFOS, and four other PFAS. The Agency selected maximum contaminant levels (MCLs) as low as 4 parts per trillion (ppt). Many participants believed that EPA’s precipitous drop from the recommended health advisory limit (in 2016) for PFOA and PFOS in drinking water of 70 ppt, to a maximum contaminant level of 4 ppt, was unjustified.

• Legal aspects of regulatory decision making: Participants noted that the proposed PFAS MCLs, if challenged in court, were likely to be upheld due to judicial deference to EPA’s scientific and regulatory expertise.

Overall, the meeting participants felt that diverse scientific perspectives should be better incorporated into US EPA’s assessments of risks to public health from PFOA, PFOS, and other PFAS.